An oncolytic herpesvirus expressing a CXCR4 antagonist interferes with glioblastoma cells’ stemness features and migration

Glioblastoma (GBM) is one of the most aggressive brain tumors. Despite the standard therapy, the survival from diagnosis remains dramatically low, especially due to tumor recurrence. Glioblastoma stem-like cells (GSCs) have been implicated in this tumor relapse, e.g., based on their capacity to escape the tumor and to migrate through the brain via CXCR4-dependent mechanisms. CXCR4 regulates biological features associated with tumor progression, including self-renewal, migration, and radio resistance. Importantly, its expression correlates with severity and poor prognosis of several cancers including GBM. The CXCR4/CXCL12 pathway therefore appears as an interesting potential therapeutic target. We have generated an oncolytic herpes simplex virus (oHSV) expressing HA-P2G, a mutated form of CXCL12 previously described as a CXCR4 competitive inhibitor. We demonstrate that, <i>in vitro</i>, oHSV/P2G impairs human GSC stemness marker expression, self-renewal, and migration. In two orthotopic xenograft murine models, oHSV/P2G intratumor injection limits tumor growth through the brain parenchyma and GSC migration through the <i>corpus callosum</i>. The ability of P2G to interfere with major GSC features demonstrates the interest in considering oHSV/P2G as a promising new therapeutic approach for GBM patients.